The present invention is directed to diester and polyester compounds for use as solubilizers and stabilizers of retinoids and methods of solubilizing and stabilizing retinoids. The diesters or polyesters of naphthalene dicarboxylic acids facilitate the delivery of the retinoids to the skin more efficiently and in a more aesthetically pleasing and less irritating manner than the organic solvents presently used, e.g., ethanol or isopropyl myristate. The present invention is directed to the use of diesters or polyesters of naphthalene dicarboxylic acids which are surprisingly effective at solubilizing the retinoids and stabilizing them such that they remain biologically active and, therefore, therapeutically effective for longer periods of time. Once solubilized in diesters or polyesters of one or more naphthalene dicarboxylic acids, the retinoids may be incorporated in topical preparations which have superior spreadability, emolliency, and skin feel and are surprisingly effective at delivering the retinoids to the skin such that they may be more biologically active, less irritating and, therefore, therapeutically more effective.
Retinoids are a class of compounds consisting of four isoprenoid units joined in a head to tail manner. All retinoids may be derived from a monocyclic parent compound containing five carbon-carbon double bonds and a functional group at the terminus of the acyclic portion (see structure below). The retinoids include Vitamin A (retinol) and its derivatives, analogues, and metabolites, both natural and synthetic, that exhibit biological activity qualitatively similar to retinol. Of particular interest to this invention are retinol, retinyl esters, retinal, and isomers of retinoic acid, including all-trans-retinoic acid (tretinoin) and cis-isomeric retinoic acids, e.g., 13-cis-retinoic acid (isotretinoin) and 9-cis-retinoic acid. The naturally occurring retinoids are essential for many of life""s processes including vision, reproduction, metabolism, differentiation, bone development, and pattern formation during embryogenesis. Retinoids comprise an important class of drugs used to treat a variety of health conditions including acne, photoaging, psoriasis, ichthyosis, hair loss, and various cancers.
It is convenient to omit the explicit representation of C and H atoms in the skeletal formulae of retinoids as follows: 
wherein R is selected from the group consisting of (1)-(10), as follows:
(1) CH2OH
(2) CHO
(3) CO2H
(4) CH3 
(5) CH2OCOCH3 
(6) CH2NH2 
(7) CHxe2x95x90NOH
(8) CHxe2x95x90N[CH2]4CHNH2CO2H
(9) CO2C2H5; and 
Retinoids are lipophilic. For example, tretinoin is practically insoluble in water, slightly soluble in ethanol (3 mg/ml) and chloroform, sparingly soluble in ether, and soluble in methylene chloride and dimethyl sulfoxide (40 mg/ml). Surprisingly, it has been found that diesters of naphthalene dicarboxylic acid are unexpectedly good solvents for retinoids. For example, isotretinoin is soluble in the diethylhexyl diester of 2,6-naphthalene-dicarboxylic acid (diethylhexyl 2,6-naphthalate, HallBrite TQ, C. P. Hall) at approximately 6.7 mg/ml, and tretinoin is soluble in the same diester at approximately 5.6 mg/ml.
Owing to their high degree of unsaturation, retinoids are extremely sensitive to UV light, air, and oxidizing agents. For example, tretinoin should be stored under an atmosphere of inert gas (e.g., argon) in the dark at  less than xe2x88x9220xc2x0 C. to preserve its integrity and biological activity. While solutions of tretinoin in pure organic solvents are stable when stored in the dark, aqueous solutions deteriorate quickly. Diesters of naphthalene dicarboxylic acid are organic in nature and extremely hydrophobic. Therefore, a solution of a retinoid such as tretinoin or isotretinoin in a diester of naphthalene dicarboxylic acid is expected to be quite stable if kept in the dark.
Commercially available preparations of retinoids typically contain ethanol in high concentrations (e.g., 55%) as the retinoid solvent. Topically applied retinoids such as tretinoin and isotretinoin are known to be quite irritating to the point where patients often discontinue therapy because the imitation becomes intolerable. Studies have indicated that the degree of irritation is dose-dependent; i.e., 0.1% isotretinoin is more irritating than 0.025% isotretinoin. This high degree of irritation has been linked to the propensity of ethanol and its solutes to be rapidly absorbed into the skin, penetrating through the epidermis and deeply into and through the dermis, resulting in an initially high and irritating concentration of retinoid. Unfortunately, studies have found that therapeutic effectiveness is also dose-dependent; i.e., 0.1% isotretinoin is more effective than 0.025% isotretinoin. Thus, patients are often faced with the unpleasant situation of choosing between optimal therapeutic effectiveness on the one hand, and low and tolerable irritation on the other.
In accordance with the present invention retinoids, such as isotretinoin, dissolved in diesters or polyesters of naphthalene dicarboxylic acid, such as diethylhexyl 2,6-naphthalate, diffuse more slowly into the skin penetrating less deeply, thereby lessening skin irritation.
Topical retinoid preparations made with diesters or polyesters of naphthalene dicarboxylic acid, such as diethylhexyl 2,6-naphthalate, are more emollient and cosmetically elegant, with a superior skin feel to other retinoid preparations. This in turn contributes to improved patient compliance because patients are more likely to apply preparations that feel good to them.
In accordance with the present invention, it has been found that diesters and/or polyesters of one or more naphthalene dicarboxylic acids can be used as a solubilizer and/or stabilizer for retinoids. Compositions containing one or more retinoids together with one or more diesters or polyesters of naphthalene dicarboxylic acids are unexpectedly less irritating and effective for topical application to skin, as a therapeutic skin enhancer.
The retinoid solubilizing/stabilizing compounds of the present invention are diesters and/or polyesters of a naphthalene dicarboxylic acid. The diesters and polyesters are reaction products of (a) a naphthalene dicarboxylic acid having the structure: 
and (b) an alcohol having the structure R1xe2x80x94OH, or a diol having the structure HOxe2x80x94R2xe2x80x94OH, or a polyglycol having the structure HOxe2x80x94R3xe2x80x94(xe2x80x94Oxe2x80x94R2xe2x80x94)mxe2x80x94OH, wherein R1 is an alkyl group, straight chain or branched, having 1 to 22 carbon atoms, R2 and R3 , same or different, are each an alkylene group, having 1 to 6 carbon atoms, and wherein m and n are each 1 to about 100, preferably 1 to about 10, more preferably 2 to about 7, or a mixture thereof.
A diester of the present invention has the structure (I): 
wherein R1 is an alkyl group, straight chain or branched, having 1 to 22 carbon atoms.
The diesters and polyesters of naphthalene dicarboxylic acids of the present invention also may have the general formula (II): 
wherein R2 and R3, same or different, are each an alkylene group having 1 to 6 carbon atoms, and n=1 to about 100, preferably 1 to about 10, more preferably 2 to about 7.
Alternatively, the diesters and polyesters of the present invention can be end-capped with an alcohol or an acid. The end-capped polyesters have the structural formula (III): 
wherein each R1, same or different, is an alkyl group having 1 to 22 carbon atoms, or a diol having the structure HOxe2x80x94R2xe2x80x94OH, or a polyglycol having the structure HOxe2x80x94R3xe2x80x94(xe2x80x94Oxe2x80x94R2xe2x80x94)mxe2x80x94OH, and, wherein R2 and R3, same or different, are each an alkylene group, straight chain or branched, having 1 to 6 carbon atoms, wherein m and n are each 1 to about 100, preferably 1 to about 10, more preferably 2 to about 7, or a mixture thereof.
These diesters and polyesters are known UV absorbents and stabilizers for a dibenzoylmethane derivative, such as PARSOL(copyright) 1789, as disclosed in this assignee""s U.S. Pat. Nos. 5,993,789; 6,180,091; 6,129,909; 6,113,931; and 6,126,925, hereby incorporated by reference.
The preferred diesters and polyesters of the present invention have a weight average molecular weight of about 244 to about 4000, and more preferably about 400 to about 1500. To achieve the full advantage of the present invention, the diester or polyester has a weight average molecular weight of about 440 to about 1000.
The naphthalene dicarboxylic acid is selected from the group consisting of 1,2-naphthalene dicarboxylic acid; 1,3-naphthalene dicarboxylic acid; 1,4-naphthalene dicarboxylic acid; 1,5-naphthalene dicarboxylic acid; 1,6-naphthalene dicarboxylic acid; 1,7-naphthalene dicarboxylic acid; 1,8-naphthalene dicarboxylic acid; 2,3-naphthalene dicarboxylic acid; 2,6-naphthalene dicarboxylic acid; 2,7-naphthalene dicarboxylic acid, and mixtures thereof. Preferred dicarboxylic acids are the 2,6-, 1,5- and 1,8-naphthalene dicarboxylic acids.
The alcohol R1xe2x80x94OH can be, for example, methanol, ethanol, propanol, isopropyl alcohol, n-butanol, sec-butanol, isobutyl alcohol, tert-butyl alcohol, amyl alcohol, 1-hexanol, 1-octanol, 1-decanol, isodecyl alcohol, 1-undecanol, 1-dodecanol, 1-tridecyl alcohol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol, 1-eicosonol, 1-decosonol, 2-ethylhexyl alcohol, 2-butyloctanol, 2-butyldecanol, 2-hexyldecanol, 2-octyldecanol, 2-hexyldodecanol, 2-octyldodecanol, 2-decyltetradecanol, and mixtures thereof.
The glycol or polyglycol can be, for example, ethylene glycol, propylene glycol, 1,2-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, tripropylene glycol, methyl propanediol, 1,6-hexanediol, 1,3-butanediol, 1,4-butanediol, PEG-4 through PEG-100, PPG-9 through PPG-34, pentylene glycol, neopentyl glycol, trimethylpropanediol, 1,4-cyclohexanedimethanol, 2,2-dimethyl-1,3-propanediol, 2,2,4,4-tetramethyl-1,3-cyclobutanediol, and mixtures thereof.
Surprisingly, these diesters and polyesters of naphthalene dicarboxylic acids are quite effective as solubilizers and stabilizers for topical application of retinoids to the skin, while providing the user with sunscreen protection, when contained in a composition in an amount of at least about 0.1% by weight, up to about 50% by weight, preferably about 0.2% to 30% by weight, more preferably about 10% to 20% by weight, based on the total weight of a composition containing one or more retinoids.
Accordingly, one aspect of the present invention is to provide a solvent/solubilizer for retinoids for topical application of retinoids, said solvent/stabilizer comprising 0.1% by weight to about 50% by weight, based on the total weight of a composition containing one or more retinoids, wherein the solvent/stabilizer comprises a diester or polyester of a naphthalene dicarboxylic acid.
Another aspect of the present invention is to provide a solubilizer/stabilizer for retinoids that also provides UV sunscreen protection and reduces the irritation to human skin resulting from topical application of retinoids.
Still another aspect of the present invention is to provide an organic solvent for retinoids capable of being emulsified together with water, such that one or more water-soluble, moisturizing components can be added to the emulsion to provide an oil-in-water or water-in-oil emulsion that reduces the irritation associated with skin contact by retinoids.
The above and other aspects and advantages of the present invention will become more apparent from the following detailed description of the preferred embodiments.
The preferred compositions of the present invention include a retinoid, including all derivatives of retinol, its analogous, and metabolites, both natural and synthetic, that exhibit biological activity qualitatively similar to retinol, in an amount of about 0.001% to about 1% by weight, preferably about 0.01% to about 0.1% by weight, and about 0.1% to 99.999%, preferably about 0.1% to about 50%, by weight of the composition, of a diester or polyester of naphthalene dicarboxylic acid having formula (I), (II) or (III). 
wherein R1 is an alkyl group, straight chain or branched, having 1 to 22 carbon atoms; 
wherein each R1, same or different, is an alkyl group having 1 to 22 carbon atoms, or a diol having the structure HOxe2x80x94R2xe2x80x94OH, or a polyglycol having the structure HOxe2x80x94R3xe2x80x94(xe2x80x94Oxe2x80x94R2xe2x80x94)mxe2x80x94OH, and, wherein R2 and R3, same or different, are each an alkylene group, straight chain or branched, having 1 to 6 carbon atoms, wherein m and n are each 1 to about 100, preferably 1 to about 10, more preferably 2 to about 7, or a mixture thereof.
The preferred retinoids that are stabilized/solubilized with the diesters or polyesters of naphthalene dicarboxylic acids, in accordance with the present, invention, include retinol; retinol palmitate; retinaldehyde; tretinoin (all-trans retinoid acid); retinol palmitate; retinoic acid, isotretinoin (13-cis retinoic acid); alitretinoin (9-cis retinoic acid); motretinide; adapalene; tazarotene; tazaroteinic acid; istretinoin; etretinate; acitretin; all-trans acitretin; 11-cis, 13-cis-12-hydroxy-methyl retinoic acid, xcex4-lactone; all-trans retinoyl xcex2-glucuronide; tamibarotene (Am-80); arotinoids; LGD 1069; fenretinide [N-(4-hydroxy-phenyl)-retinamide]; E 5166 (polyprenoic acid); CD 2398; mefarotene (Ro 40-8757); and mixtures thereof.